Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Christopher Duncan; Benjamin Thompson; Rui Chen; Gillian Rice; Florian Gothe; Dan Young; Simon Lovell; Victoria Shuttleworth; Vicky Brocklebank; Bronte Corner; Andrew Skelton; Vincent Bondet; Jonathan Coxhead; Darragh Duffy; Cécile Fourrage; John Livingston; Julija Pavaine; Edmund Cheesman; Stephania Bitetti; Angela Grainger; Meghan Acres; Barbara Innes; Aneta Mikulasova; Ruyue Sun; Rafiqul Hussain; Ronnie Wright; Robert Wynn; Mohammed Zarhrate; Leo Zeef; Katrina Wood; Stephen Hughes; Claire Harris; Karin Engelhardt; Yanick Crow; Richard Randall; David Kavanagh; Sophie Hambleton; Tracy Briggs

doi:10.1126/sciimmunol.aav7501

Journal articles

Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Christopher Duncan ^{1, *} Benjamin Thompson ¹ Rui Chen ¹ Gillian Rice ² Florian Gothe ^{1, 3} Dan Young ⁴ Simon Lovell ² Victoria Shuttleworth ¹ Vicky Brocklebank ¹ Bronte Corner ¹ Andrew Skelton ¹ Vincent Bondet ⁵ Jonathan Coxhead ¹ Darragh Duffy ⁵ Cécile Fourrage ⁶ John Livingston ⁷ Julija Pavaine ^{8, 2} Edmund Cheesman ⁸ Stephania Bitetti ⁸ Angela Grainger ¹ Meghan Acres ¹ Barbara Innes ¹ Aneta Mikulasova ¹ Ruyue Sun ¹ Rafiqul Hussain ⁵ Ronnie Wright ^{2, 8} Robert Wynn ⁹ Mohammed Zarhrate ¹⁰ Leo Zeef ² Katrina Wood ¹¹ Stephen Hughes ^{9, 8} Claire Harris ¹ Karin Engelhardt ¹ Yanick Crow ^{10, 12, 13} Richard Randall ⁴ David Kavanagh ^{1, 11} Sophie Hambleton ^{1, 11, *} Tracy Briggs ^{2, 8, *}

* Corresponding author

1 Newcastle University [Newcastle]

2 University of Manchester [Manchester]

3 LMU - Ludwig-Maximilians-Universität München

4 University of St Andrews [Scotland]

5 Immunobiologie des Cellules dendritiques

6 Institut des Maladies Génétiques Imagine [Paris]

7 University of Leeds

8 Central Manchester University Hospitals NHS Foundation Trust

9 Royal Manchester Children's Hospital

10 IMAGINE - U1163 - Imagine - Institut des maladies génétiques

11 Newcastle Upon Tyne Hospitals NHS Foundation Trust

12 UPD5 - Université Paris Descartes - Paris 5

13 University of Edinburgh

Abstract : Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Immunology

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https://hal-pasteur.archives-ouvertes.fr/pasteur-02430168
Contributor : Marie-Christine Vougny <>
Submitted on : Tuesday, January 7, 2020 - 10:36:53 AM
Last modification on : Tuesday, October 20, 2020 - 1:04:02 PM

Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

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